Transdermal delivery of drugs or therapeutic agents is an important medicament administration route. Transdermal drug delivery bypasses gastrointestinal degradation and hepatic metabolism, while at the same time providing slow, but controlled, systemic delivery of a drug or an agent to a patient's blood stream. It is an especially attractive administration route for drugs or agents with a narrow therapeutic index, short half-life and potent activity.
Transdermal permeation of most compounds is a passive diffusion process. The maximum flux of agent through a patient's skin, i.e., the quantity of agent delivered through a given area of skin, is primarily determined by the drug's partition coefficient and solubility characteristics. Transdermal permeation, however, can be enhanced by iontophoresis.
Iontophoresis is a process by which the transdermal transport of therapeutic agents or drug is increased or controlled using electro-repulsion as the driving force. By the application of an external electrical field to, e.g., an agent-containing reservoir of an electrotransport device, drugs or agents of like charge are driven by repulsive forces through the skin. As such, the transdermal delivery becomes a more controllable, rather than a passive, process, and agent or drug transport flux is thereby increased.
Iontophoretic devices have been known since the early 1900's. A 1934 British Patent Specification No. 410,009 describes a portable iontophoretic device which overcame one of the disadvantages of earlier devices, namely that the patient needed to be immobilized near the current source. More recently, a number of United States patents have issued in the iontophoresis field, indicating a renewed interest in this mode of drug delivery. For example, Vernon et al., U.S. Pat. No. 3,991,755; Jacobsen et al., U.S. Pat. No. 4,141,359; Wilson, U.S. Pat. No. 4,398,545; and Jacobsen, U.S. Pat. No. 4,250,878, disclose examples of iontophoretic devices and some applications thereof.
In presently known iontophoresis devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the "active" or donor electrode, is the electrode from which the ionic (or ionizable) agent, drug precursor or drug is delivered into the body via the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery.
Depending upon the electrical charge of the species to be delivered transdermally, either the anode or cathode may be the "active" or donor electrode. If, for example, the ionic substance to be driven into the body is positively charged, then the anode will be the active electrode and the cathode will serve to complete the circuit. On the other hand, if the ionic substance to be delivered is relatively negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Alternatively, both the anode and the cathode may be used to deliver drugs of appropriate charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anodic electrode can drive positively charged substances into the body while the cathodic electrode can drive negatively charged substances into the body.
Existing iontophoresis devices generally require a reservoir or source of the ionized or ionizable species (or a precursor of such species) which is to be iontophoretically delivered or introduced into the body. Examples of such reservoirs or sources of ionized or ionizable species include a pouch as described in the previously mentioned Jacobsen, U.S. Pat. No. 4,250,878, a pre-formed gel body as disclosed in Webster, U.S. Pat. No. 4,382,529, and a generally conical or domed molding of Sanderson et al., U.S. Pat. No. 4,722,726. Such drug reservoirs are electrically connected to the anode or to the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species or agents.
More recently, iontophoretic delivery devices have been developed in which the donor and counter electrode assemblies have a "multi-laminate" construction. In these devices, the donor and counter electrode assemblies are each formed by multiple layers of (usually) polymeric matrices. For example, Parsi, U.S. Pat. No. 4,731,049, discloses a donor electrode assembly having hydrophilic polymer based electrolyte reservoir and drug reservoir layers, a skin-contacting hydrogel layer, and optionally one or more semipermeable membrane layers. In addition, Ariura et al., U.S. Pat. No. 4,474,570, discloses a device wherein the electrode assemblies include a conductive resin film electrode layer, a hydrophilic gel reservoir layer, and aluminum foil conductor layer and an insulating backing layer.
Hydrogels have been particularly favored for use as the drug reservoir matrix and electrolyte reservoir matrix in iontophoretic delivery devices, in part, due to their high equilibrium water content and their ability to quickly absorb water. In addition, hydrogels tend to have good biocompatibility with the skin and with mucosal membranes.
Iontophoresis has been used for both the local and systemic delivery of drugs. The iontophoresis process has been useful in the transdermal administration of any number of medicaments or drugs. The control of electrical factors, such as intensity, profile and duration of electrical current application, as well as physicochemical factors, such as the pH or ionic strength, allows one to modulate the rate and the duration of permeation. As intended herein, the particular therapeutic agent to be delivered may be completely charged (i.e., 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, electroosmosis or a combination of the two. Electroosmosis, in general, results from the migration of solvent, in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir.
Of particular interest is the transdermal delivery of analgesic drugs for the systemic management of moderate to severe pain. Control of the rate and duration of drug delivery is particularly important for systemic transdermal delivery of analgesic drugs to avoid the potential risk of overdose and the discomfort of an insufficient dosage.
One class of analgesics that has found application in a transdermal delivery route is the synthetic opiates, a group of 4-aniline piperidines. The synthetic opiates, e.g., fentanyl and certain of its derivatives such as sufentanil and alfentanyl, are particularly well-suited for transdermal administration. These synthetic opiates are characterized by their rapid onset of analgesia, high potency, and short duration of action. They are estimated to be 80 and 800 times, respectively, more potent than morphine. These drugs, in the form utilized, are weak bases, i.e., amines, whose major fraction is cationic in acidic solution. Further, these drugs or agents have polybasic anionic counter ions e.g, citrate, tartrate, and maleate.
The amine drugs preferably used in this invention are available pharmaceutically as citrates, e.g., fentanyl citrate, sufentanil citrate. In vitro and in vivo studies of iontophoretic delivery of these analgesic citrates have been reported. See, e.g., Thysman and Preat, Anesth. Analg., vol. 77 (1993) 61-66. In an in vivo study to determine plasma concentration, Thysman and Preat compared simple diffusion of fentanyl and sufentanil to iontophoretic delivery in citrate buffer at pH 5. Simple diffusion did not produce any detectable plasma concentration. The plasma levels attainable depended on the maximum flux of the drug that can cross the skin and the drug's pharmacokinetic clearance variables. Iontophoretic delivery was reported to have a significantly reduced lag time (i.e., time required to achieve peak plasma levels) as compared to passive transdermal patches (1.5 h versus 14 h). Thus, active electrotranstophoretic delivery of drugs over passive delivery of these drugs, many issues remain. For example, fentanyl, in acidic solution exists as the cation FH.sup.+ where F represents fentanyl. Fentanyl citrate, a pharmaceutically available form of fentanyl having a polybasic citrate anion, appears to involve only one of the three carboxylic acid groups of citric acid in salt formation with the fentanyl. At the pH for optimized permselectivity of skin, namely, pH.congruent.6.0, the remaining two carboxylic acid groups are ionized and the protons (H.sup.+) generated in ionization compete with FH.sup.+ for delivery in the electrotransport process. This competition reduces the overall efficiency of delivery of FH.sup.+ agent.
Previous work has involved the neutralization of fentanyl citrate with bases such as sodium or potassium hydroxide. It has been found that such neutralizations of fentanyl citrate with sodium or potassium hydroxide, achieve little more than introducing another small monovalent cation which, similar to protons, competes with fentanyl cation for delivery during an electrotransport process.
To date, the art has not adequately responded with a solution to this problem of reducing competitive ions in the electrotransport process.